Patent GB-449379-A (GB)
Title: Process for the manufacture of derivatives of sterols
IPC: C07J75/00
Filed: 1934-11-22
Abstract: Derivatives of unsaturated sterols which are neutral unsaturated polycyclic ketones possessing a cyclopentano-polyhydro-phenanthrene nucleus and some of which have sex hormone action are prepared by the oxidation of those sterols which contain at least one double bond in the cyclopentanophenanthrene nucleus.  The derivatives are isolated from the neutral portion of the oxidation product and are represented by the general formula <FORM:0449379/IV/1> where R represents an (OH) group or a group which upon hydrolysis is converted into an (OH) group such as O-acyl, O-alkyl, O-aryl, or halogen, and X represents either >C=O or <FORM:0449379/IV/2> A mixture of compounds, may be produced in the oxidation; in some of which X has one, and in some the other of the above meanings. Examples of sterols which may be used as starting materials are cholesterol, phytosterol, stigmasterol, sitosterol and cinchol. Examples of suitable oxidizing agents are chromium trioxide, chromium oxychloride, bichromates, and permanganates.  It is preferred that the double bond in the nucleus should be protected by, for instance, the addition of halogen or halogen hydride during the oxidation.  In all cases the protecting agent is removed after the oxidation, by, in the case of halogen, agents such as zinc dust, sodium amalgam, or metallic nickel and in the case of halogen hydride, by alkaline agents such as potassium hydroxide, pyridine, sodium iodide in acetone and alkali acetate. The hydroxy group of the sterol may also be protected by esterification, etherification, or halogenation.  The neutral products are isolated from the oxidation product by treatment with an alkaline solution followed by extraction with a solvent. The required ketones may then be extracted from the neutral fraction by (a) a process which depends on the different solubility of the different products, such as fractional crystallization or precipitation, (b) fractional distillation or sublimation in a high vacuum, (c) the use of a compound capable of forming with the ketones a reaction product of different solubility such as semicarbazide, thiosemicarbazide, hydroxylamine, phenylhydrazine and substituted phenylhydrazines, together with benzhydrazides and quaternary ammonium acetohydrazides, such as trimethyl - aceto - hydrazide - ammonium chloride, (d) fractional crystallization or precipitation with ketone reagents. Methods (a), (c) and (d) are particularly suitable for separating ketones of the C19 from those of the C21 series.  The above separation methods may be used either singly or in conjunction with one another.  In examples: (1) stigmasterol acetate is brominated in carbon tetrachloride solution, the product oxidized by chromium trioxide, and the oxidation product debrominated by zinc dust.  The acid portion is removed by treatment with alkali and the ketones isolated by semicarbazide.  The fractional crystallization of the semi-carbazides results in the isolation of dehydroandrosterone and pregnenolone.  The latter compound may be converted to the corpus luteum hormone pregnendione by oxidation; (2) the same as example (1) except that calcium permanganate is the oxidizing-agent; (3) cholesterol acetate dibromide is oxidized in glacial acetic acid solution by chromic acid, and the ketone isolated as in example (1); (4) the acetates of the sterols of soya bean oil are brominated and the tetrabromo stigmasterol acetate separated and oxidized in glacial acetic acid solution with chromic acid.  The product is worked up as in example (1); (5) methoxy cholesterol is brominated and oxidized in glacial acetic acid solution with chromic acid, and worked up as in example (1); (6) dibromo-cholesterol benzoate is oxidized as in example 5, the product is debrominated with zinc dust and treated with petroleum ether.  The undissolved portion is crystallized from alcohol to effect the separation of the ketones of the C19 and the C21 series; (7) cholesterol acetate in glacial acetic acid solution is treated with hydrogen chloride, the precipitate of aceto-cholesterol-hydrochloride filtered off, oxidized and worked up as in example (1), except that potassium hydroxide is used to remove the hydrogen chloride protecting agent; (8) as in example (7) except that pyridine is used to remove hydrogen chloride; (9) sitosterol acetate dibromide is treated as described in example (1); (10) cholesteryl chloride is treated as described in example (1) and the corresponding chlor-ketone isolated and converted by hydrolysis into the corresponding hydroxy ketone.  Specifications 445,189 and 447,498 are referred to.